Genes and pathways monotonically dysregulated during progression from normal through leukoplakia to gingivo-buccal oral cancer

Debodipta Das,Sandip Ghose,Chinmay K Panda,Bidyut Roy,Rajiv Sarin,Arindam Maitra,Partha P Majumder

doi:10.1038/s41525-021-00195-8

Abstract

Oral squamous cell carcinoma of the gingivo-buccal region (OSCC-GB) accounts for the highest cancer morbidity and mortality among men in India. It has been observed that about one-third of individuals with oral leukoplakia, a dysplastic precancerous lesion in the oral cavity, progress to oral cancer. We aimed to identify systematic transcriptomic changes as a normal tissue in the oral cavity progresses to frank OSCC-GB. Seventy-two OSCC-GB patients, from multiple hospitals, were recruited, and transcriptome analysis of tumor and adjacent normal tissue (of all patients) and adjacent leukoplakia tissue (of a subset of 25 unselected patients with concomitant leukoplakia) was performed. We have identified many differences in the transcriptomic profiles between OSCC-GB and squamous cell carcinoma of the head and neck regions. Compared to the normal/precancerous tissue, significant enrichment of ECM−receptor interaction, PI3K-Akt signaling, cytokine−cytokine receptor interaction, focal adhesion, and cell cycle pathways were observed in OSCC-GB. Using gene set enrichment analysis, we identified a profound role of interferon receptor signaling in tumor growth by activating immune evasion mechanisms. The role of tumor-infiltrating immune cells further supported the growth and immunosuppressive mechanism of tumor tissues. Some immune evasion genes—CD274, CD80, and IDO1—were found to be activated even in the precancerous tissue. Taken together, our findings provide a clear insight into the sequential genetic dysregulation associated with progression to oral cancer. This insight provides a window to the development of predictive biomarkers and therapeutic targets for gingivo-buccal oral cancer.

Highlights

Of all cancers, cancer of the oral cavity and lip is known to be associated with the highest morbidity and mortality among men in India[1]
Significantly differentially expressed between (b) patients derived from gingivo-buccal oral cancer (OSCC-GB) and head and neck cancer (TCGA-head and neck squamous cell carcinoma (HNSC)). c OSCC-GB development and three-group (TvLvN) comparisons d leukoplakia vs. normal (LvN), tumor vs
The ESTIMATE scores of all, but one, of the OSCC-GB tumor samples of this study are within the range of ESTIMATE scores of the head and neck squamous cell carcinoma (HNSC) tumor samples included in the TCGA study (Supplemental Table S1)

Summary

Introduction

Cancer of the oral cavity and lip is known to be associated with the highest morbidity and mortality among men in India[1]. Squamous cell carcinoma is the predominant histologic form in the oral cavity[2]. The most commonly affected site of oral squamous cell carcinoma, in the Indian subcontinent, is the gingivo-buccal region (OSCC-GB), which includes buccal mucosa, gingivo-buccal sulcus, lower gingiva, and retromolar trigone[3,4]. OSCC-GB is associated with a poor prognosis due to delayed presentation because of fear of being forced to quit tobacco on detection of disease. Despite recent advancements in cancer treatment, the overall 5-year survival rate for all stages of oral cancer is low (~60%)—which further lowers if there are regional or distant metastases[5]. Adjuvant postoperative radiotherapy with or without chemotherapy is offered while considering multiple risk factors including comorbidities, pathologic staging, and nodal involvement[2]

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